Abstract

Objectives: To study blood glucose levels in elective neurosurgical patients between those who received preoperative dexamethasone and those who did not receive dexamethasone. To study the incidence of required treatment to correct blood glucose levels.

Methods: The prospective observational study was conducted in 255 patients undergoing an elective craniotomy from December 2015
through August 2017. They were categorized into two groups according to preoperative dexamethasone administration. The blood glucose
level was classified into three levels as hypoglycemia (less than 80 mg/dL), normal (80-180 mg/dL), and hyperglycemia (more than 180 mg/
dL).

Results: The 255 patients were classified into the dexamethasone group (158 patients) and the non-dexamethasone group (97 patients).
Hypoglycemia and treatment requirements were significantly greater in the non-dexamethasone group than the patients who received
dexamethasone preoperatively, 30% vs 6%, p< 0.01. Within four hours after surgery and between eight to 24 hours after surgery, hyperglycemia
was significantly high in the dexamethasone group, 24% vs. 12% (p 0.023) and 8% vs. 1% (p 0.014), respectively.

Conclusion: The incidence of abnormal blood glucose was high in neurosurgical patients. Frequent blood glucose monitoring is mandatory
for proper management during the perioperative neurosurgery period.

Keywords: Dexamethasone; Blood Glucose; Craniotomy; Perioperative;

Introduction

The effect of hyperglycemia on brain function is harmful as the
brain is absolutely dependent on a continuous glucose supply [1]. The
deleterious effects of hyperglycemia occur at the molecular level and
in the clinical presentation. Hyperglycemia disrupts the integrity of the
blood brain barrier (BBB) and worsens cerebral edema [2]. In the setting
of pre-existing neurological injury, hyperglycemia decreases the ischemic
threshold of neurons which could burden brain ischemia [3]. Clinically,
hyperglycemia induces a hyperosmolar state and osmotic diuresis. The
patients are at risk for hypovolemia, electrolyte imbalances, mental
status changes, or seizures [1]. The stress-induced hyperglycemia refers
to an increased level of the blood glucose response to insulin counterregulatory
hormones (cortisol, glucagon, epinephrine, growth hormone)
and pro-inflammatory cytokines (interleukin-1, interleukin-6, and tumor
necrosis factor-alpha) [4,5]. Perioperative hyperglycemia is considered
as one of the surgical stress responses to surgery. The blood glucose is
markedly exaggerated in poorly controlled diabetes mellitus. Controlling
blood glucose levels in neurosurgical patients results in a lower rate of
craniotomy wound infections, shortened lengths of hospital stay, reduced
hospital costs, and overall clinical outcomes [6,7].

Dexamethasone is a glucocorticoid with minimal mineral corticoid
effect. It is used to reduce the peritumoral vasogenic edema in the
intracranial compartment. The beneficial effects at the molecular level,
radiologic findings, and clinical symptoms occur within hours [8]. The
mechanisms of action are promoting Ang-1, the blood-brain barrier (BBB)
stabilizing factors and clearing the extracellular fluid into the ventricular
system [9,10]. Dexamethasone down regulates vascular endothelial
growth factor (VEGF) and basic fibroblast growth factor (bFGF), the
angiogenic factors that lead to losing endothelial cell junctions in tumor
blood vessels [11,12]. Although glucocorticoids have many potential
beneficial effects, they have various systemic complications. The most
common endocrine complication of dexamethasone is hyperglycemia.
However, all of the complications are dose-related. Despite decreasing
vasogenic edema of the tumor, a single 10-mg dose of dexamethasone
administered in nondiabetic patients significantly increases the blood
glucose concentrations over a four-hour period [13]. Monitoring of the
blood glucose concentrations for at least 12 hours in all neurosurgical
patients with newly administered dexamethasone was suggested [14]. The
purpose of the present study was to compare the incidence of abnormal
blood glucose levels in neurosurgical patients who received preoperative
dexamethasone with patients who did not receive dexamethasone. The
treatment episodes for hypoglycemia and hyperglycemia were compared.

Methods

After approval from the Institutional Ethics Committee, 313 patients
undergoing an elective craniotomy during December 2015 through August
2017 were recruited. The study design was a prospective observation.
Dexamethasone was ordered exclusively by the neurosurgeon. The
frequency of blood glucose measurements and the decision of treatment
depended on the attending anesthesiologist, who was not involved in
the study. Exclusion criteria were the patients younger than 18 years old,
previously diagnosed diabetes mellitus, and without fasting overnight.
Candidates who had the overall perioperative blood glucose measurements
less than seven times or received additional corticosteroids during surgery
were excluded. The anesthetic records and postoperative records of the
remaining patients were reviewed.

Time points of measurement and blood glucose levels data were
extracted. The seven time points of blood glucose measurement were
the average blood glucose during each specific interval. T1 was the first
obtained blood glucose before the surgery, T2 and T3 were the blood
glucose measured in the first to the second hours and the third to the
fourth hours of surgery, T4 was blood glucose measured before the end
of surgery. T5 was the blood glucose obtained within the first four hours
after surgery. T6 was the blood glucose obtained within the fourth to the
eighth hour after surgery. T7 was the average of blood glucose measured
during the eighth to the twenty-fourth hour after surgery.

Intra-arterial catheter placement to monitor blood pressure was
performed in all neurosurgical patients. Arterial blood sampling was
obtained intermittently during the intraoperative and postoperative
period using a gluco-strip and a glucometer device. Anesthetic technique
and anesthetic drugs were not controlled in this study. Anesthetic
maintenance could be volatile-based in air: oxygen mixture or total
intravenous anesthesia (TIVA) technique. The choice of intravenous
fluid was managed solely by the attending anesthesiologist. The blood
glucose levels were arbitrarily categorized into three groups, less than
80 mg/dL, 80-180 mg/dL, and more than 180 mg/dL as hypoglycemia,
normoglycemia, and hyperglycemia, respectively [15].

The primary outcome was the incidence of abnormal blood glucose
at any time point during the intraoperative and the first 24-hour
postoperative periods among patients who received and did not receive
dexamethasone. The secondary outcome was the episode of required
treatment with dextrose solution or insulin in perioperative period.

Statistical Analysis

The nominal data were presented as number and percentage, then Chisquare
or Fisher’s exact tests were used to assess statistical differences.
Non-normally distributed BG values were presented as median with range
and then the statistical difference between groups was tested with Mann-
Whitney U test, and the difference related within the group was analyzed
with Friedman test. Statistical Package for the Social Science, version
20 (SPSS 20, IBM, Armonk, NY, USA) was used to perform statistical
analysis, with p-values < 0.05 considered statistically significant.

Results

Among 313 patients, fifty-eight were excluded because of the
incomplete perioperative blood glucose measurements. The remaining
255 patients were classified in the dexamethasone group (158 patients) and
the non-dexamethasone group (97 patients). Within the dexamethasone
group, 105 patients (67%) received dexamethasone in the 24-48 hours
preoperatively, and the remainder received it 48-96 hours before surgery.
Table 1 shows patient characteristics, Glasgow coma scale (GCS)
score, history of previous steroid use, and anesthetic technique. The
distribution of American Society of Anesthesiology (ASA) classification
and diagnosis were different between patients who received and did not
receive dexamethasone. A significantly greater number of patients in
dexamethasone group were diagnosed with a tumor, 97% versus 61%, p
< 0.01.

There was no patients received dextrose-containing fluid as
maintenance. Fluid with dextrose was administered only in patients
who were diagnosed of hypoglycemia. The result in Table 2 showed that
there were a high number of patients in whom hypoglycemia had been
documented but not received dextrose. Those patients were followed
up blood glucose within an hour later. The correction was done after
the consecutive episodes of hypoglycemia. Some of them turned to
normoglycemia or even hyperglycemia.

Table 2 shows the variation of abnormal blood glucose and the
required treatment episodes at different time points. Before surgery,
hypoglycemia and treatment requirement were significantly greater in
non-dexamethasone group than the patients who receive dexamethasone
preoperatively, 30% vs 6%, p< 0.01. Within four hours after surgery
and between the 8th to 24th hours after surgery, hyperglycemia was
significantly higher in the dexamethasone group, 24% vs 12% (p 0.023)
and 8% vs 1% (p 0.014), respectively. Hypoglycemia and the episode of
dextrose requirements in non-dexamethasone group were higher than
patients receiving dexamethasone. Unlike, hyperglycemia and insulin,
treatments were greater in the dexamethasone group.

Figure 1 shows the parallel columns of blood glucose level classified
as hypoglycemia, normoglycemia, and hyperglycemia between the groups
of dexamethasone and non-dexamethasone receiving patients. Gradually
increase of blood glucose level was markedly noticed in both groups.
However, the degree of blood glucose increments was greater in patients
receiving dexamethasone.

Figure 2 shows the gradual, but significantly increased median blood
glucose in both groups. Blood glucose obtained in the pre-surgical period
was 113 mg/dl then rose to 147 mg/dl in the fourth hour after surgery,
p< 0.01, in the dexamethasone group. Similar findings were revealed in the
non-dexamethasone group, 87 mg/dl to 139 mg/dl, p< 0.01.

Discussion

This study shows that preoperative dexamethasone in non-diabetic
patients undergoing a craniotomy cause’s significant increase of blood
glucose during surgery and postoperative period. The incidence of
hyperglycemia increased from approximately 5% during the operation
to 24% in the 4-hours postoperatively. This finding supports a previous
report by Pasternak et al [13]. The authors stated that a single dose of
dexamethasone during craniotomy could significantly increase blood
glucose over a four-hour period [13]. In spite of no dexamethasone
administration, intraoperative hyperglycemia has been shown in patients
undergoing elective craniotomy due to a hypermetabolic stress response
[14,16]. In this study, the blood glucose levels increased over four hours of
neurosurgery and rose in the first four hours postoperatively. A study with
traumatic brain injured patients reported an incidence of hyperglycemia
(defined as blood glucose>150mg/dl) of 45%, and severe hyperglycemia
(blood glucose>200mg/dl) of 15% [17]. The reported incidences
were diverse across previous studies, and depended on the levels of
blood glucose defined as hypoglycemia, hyperglycemia, and severe
hyperglycemia [18,19]. The results of this study affirmed the essential of
frequent monitoring blood glucose level in neurosurgical patients. Certain
anesthetic drugs have specific effects on blood glucose levels. Propofol
attenuates the stress response, decreases cerebral metabolic rate of oxygen
and glucose metabolism, but volatile anesthetics decrease insulin secretion
and increase blood glucose levels [1,20,21]. In this study, similar ratios
of patients in the dexamethasone and the non-dexamethasone groups
received propofol-based TIVA technique.

Figure 1: Percentage of patients in each blood glucose level (y axis)in group dexamethasone (Grp Dex): the first column of each pair, compared to group non-dexamethasone (Grp Non-DEX): the second column of each pair at different time intervals (x axis)Abbreviations: IBS: intraoperative blood sugar, POBS: postoperative blood sugar

Figure 2: Box-plot diagramof blood glucose concentration ingroup dexamethasone, compared to group non-dexamethasone showing the median and the interquartile range and the outliers at different time intervals (x axis)

Sharma D et al. explained that the concern of hypoglycemia caused a
shortage of insulin administration during anesthesia, even when glucose
values exceeded 200 mg/dL [27]. This study showed six patients with blood
glucose exceeding 180 mg/dL. Only one of them received insulin infusion
during surgery when the follow-up plasma glucose rose to 364 mg/dL.
Although stress response hyperglycemia is common in neurosurgical
patients, hypoglycemia still occurs and is usually under-recognized [28].
Therefore, blood glucose levels should be frequently checked in patients
undergoing neurosurgery, not only the diabetes or steroid-receiving
patients, but also to detect hypoglycemia in prolonged fasting patients
without glucose-containing fluid infusion [29]. Otherwise 80 ml/hour of
5% dextrose solution should be given to prevent hypoglycemia [29]. This
study found substantial hypoglycemia in non-dexamethasone patients
compared to the other group (30% vs 6%). One-third of hypoglycemia
patients were infused with 5% dextrose in 0.9% saline (5% D/NSS)
solution during anesthetic maintenance, in rate of 1.5 ml/kg body weight.
However, after the operation started, the occurrence of hypoglycemia
decreased remarkably in both groups.

The limitations of this study include the definitive diagnosis of diabetes
mellitus and the treatment effect, either dextrose infusion or insulin
administration, to subsequent blood glucose levels. Some neurosurgical
patients have unrecognized diabetes. To clearly diagnose diabetes mellitus,
Hemoglobin A1C should be tested in patients who had a baseline blood
glucose greater than 180 mg/dl. Moreover, no other stress hormones
related to hyperglycemia were measured, so it was inconclusive whether
dexamethasone was the only causative factor of hyperglycemia during
perioperative craniotomy.

Conclusion

Patients with preoperative dexamethasone administration incurred
hyperglycemia during an elective craniotomy. Blood glucose level reached
the highest point in the first four postoperative hours. The incidence
of hypoglycemia was detected in non-dexamethasone, neurosurgical
patients receiving dextrose-free solution. Therefore, frequent blood
glucose monitoring is mandatory for proper management during the
perioperative neurosurgery period.

Ethics Approval

The study was approved by the Institutional Ethics Review Board,
Faculty of Medicine, Chiang Mai University, with the study protocol
number of ANE-2558-03463 and the Ethics number of 486/2558.

Acknowledgement

The authors gratefully acknowledge assistance with statistical analyses
by Mrs. Rochana Phuackchantuc of the Research Administration, Faculty
of Medicine, Chiang Mai University.